There are presently no approved drug therapies for type 2 diabetes mellitus (T2DM) that operate by directly stimulating the release of glucagon-like peptide-1 (GLP-1) from intestinal L-cells. Identifying such potentially antidiabetogenic agents would be highly significant due to the fact that intestinally released GLP-1 enhances pancreatic insulin secretion while also slowing gastric emptying and suppressing appetite. In particular, we expect that orally administered GLP-1 secretagogues would constitute an entirely new class of blood glucose-lowering agents. Unlike currently available GLP-1 mimetics (e.g., exenatide), they would not require subcutaneous injection, and when combined with DPP-4 inhibitors that extend the half-life of GLP-1 (e.g., sitagliptin), they would raise levels of circulating GLP-1 substantialy. We have preliminary data that indicate several of our proprietary cycloalka[b]indoles can induce the secretion of GLP-1 in mSTC-1 cells with good EC50 levels. These are small-molecule compounds that may potentially be orally administrable. The objectives for this collaborative proposal (see letters of support from Eli Lilly and Prof. George Holz; SUNY Upstate Medical University) are to invent novel chemical methods (and their asymmetric variants) for accessing cycloalka[b]indoles which we will then use for protein target identification and the discovery of more potent GLP-1 secretagogues. Our central hypothesis is that we can rapidly access cyclopenta-, cyclohexa- and cyclohepta[b]indoles through a common indolyl carbocation intermediate. In the presence of appropriate 2-, 3-, or 4-carbon coupling partners, indolyl carbocations will undergo (3+2), (3+3), and (3+4) formal cycloaddition reactions to furnish the desired products. These objectives will be accomplished by carrying out the following specific aims: 1) develop new annulation methods for indole and related heterocycles, 2) develop asymmetric annulation reactions of indole and related heterocycles, and 3) determine the biological target of these GLP-1 secretagogues and identify more potent analogues. The significance of this proposal to human health is that it will lead to the identification of new molecular entities that can induce the up-regulation of GLP-1 release. This is the initial step towards our long-term goal of developing the 1st T2DM therapeutic based on increasing GLP-1 levels. This research is innovative because it exploits under-utilized indolyl carbocations as key reactive intermediates in novel three-component coupling reactions for the rapid syntheses of cycloalka[b]indoles. We will validate this methodology by featuring it as the key step in the 1st total synthesis of fischerindole L. We will also develop the 1st example of an enantioselective (4+3) cycloaddition reaction of oxyallyl or aminoallyl cations catalyzed by chiral Bronsted acids. Moreover, cycloalka[b]indoles and other similar heterocycles have been targeted as potential drug candidates for numerous other indications. Therefore, an additional potential positive impact of this work is its application to the syntheses and identification of drug candidates in non-T2DM therapeutic areas.